Revision of T cell receptor chain genes is required for normal T lymphocyte development

To become mature T cells, developing thymocytes must first assemble a T cell receptor (TCR) chain gene encoding a TCR chain that forms a pre-TCR. These cells then need to generate a TCR chain gene encoding a TCR chain, which, when paired with the TCR chain, forms a selectable TCR. Newly generated VJ rearrangements that do not encode TCR chains capable of forming selectable TCRs can be excised from the chromosome and replaced with new VJ rearrangements. Such replacement occurs through the process of TCR chain gene revision whereby a V gene segment upstream of the VJ rearrangement is appended to a downstream J gene segment. A multistep, gene-targeting approach was used to generate a modified TCR locus (TCR sJ) with a limited capacity to undergo revision of TCR chain genes. Thymocytes from mice homozygous for the TCR sJ allele are defective in their ability to generate an TCR. Furthermore, those thymocytes that do generate an TCR have a diminished capacity to be positively selected, and TCR sJ/sJ mice have significantly reduced numbers of mature T cells. Together, these findings demonstrate that normal T cell development relies on the ability of developing thymocytes to revise their TCR chain genes.